Bottom Line:
In airway epithelial cells, inhibition of IPO13 expression prevents nuclear entry of GR and abrogates anti-inflammatory effects of glucocorticoids.This improvement was similar to that among children treated with long-term inhaled corticosteroids.IPO13 variation is associated with improved AHR in asthmatic children.

Background: Glucocorticoid function is dependent on efficient translocation of the glucocorticoid receptor (GR) from the cytoplasm to the nucleus of cells. Importin-13 (IPO13) is a nuclear transport receptor that mediates nuclear entry of GR. In airway epithelial cells, inhibition of IPO13 expression prevents nuclear entry of GR and abrogates anti-inflammatory effects of glucocorticoids. Impaired nuclear entry of GR has been documented in steroid-non-responsive asthmatics. We hypothesize that common IPO13 genetic variation influences the anti-inflammatory effects of inhaled corticosteroids for the treatment of asthma, as measured by change in methacholine airway hyperresponsiveness (AHR-PC20).

Methods: 10 polymorphisms were evaluated in 654 children with mild-to-moderate asthma participating in the Childhood Asthma Management Program (CAMP), a clinical trial of inhaled anti-inflammatory medications (budesonide and nedocromil). Population-based association tests with repeated measures of PC20 were performed using mixed models and confirmed using family-based tests of association.

Results: Among participants randomized to placebo or nedocromil, IPO13 polymorphisms were associated with improved PC20 (i.e. less AHR), with subjects harboring minor alleles demonstrating an average 1.51-2.17 fold increase in mean PC20 at 8-months post-randomization that persisted over four years of observation (p = 0.01-0.005). This improvement was similar to that among children treated with long-term inhaled corticosteroids. There was no additional improvement in PC20 by IPO13 variants among children treated with inhaled corticosteroids.

Conclusion: IPO13 variation is associated with improved AHR in asthmatic children. The degree of this improvement is similar to that observed with long-term inhaled corticosteroid treatment, suggesting that IPO13 variation may improve nuclear bioavailability of endogenous glucocorticoids.

Mentions:
The ten IPO13 SNPs evaluated in this study were selected from build 119 of dbSNP in order to achieve an average spacing of approximately 1 SNP every 5 kb across the IPO13 locus and its 20 kb flanking sequence (Figure 1a). Among non-Hispanic whites, all 10 SNPs had a minor allele frequency (MAF) of at least 0.05, and pair-wise LD high (median pair-wise D' 0.99, interquartile range of 0.98–1.0; see Figure 1b), suggesting very limited haplotype diversity. Indeed, the 10 SNP form only four common haplotypes (Figure 1c), which can be unambiguously classified by several possible combinations of three tagging-SNPs (one representative set denoted with arrowheads in Figure 1c). The genotyped SNP capture nearly all reported common variation at the IPO13 locus, in that they efficiently tag (r2 > 0.80) all but two of the 21 SNPs with available genotype information in the HapMap families of northern and western European ancestry. This high degree of LD implies substantial redundancy with regard to the number of independent observations made in the association studies to be described below. Using the spectral decomposition of matrices (see Methods and references [25] and [26]) we estimated that the 10 genotyped variants effectively represent only 6 independent markers for association testing.

Mentions:
The ten IPO13 SNPs evaluated in this study were selected from build 119 of dbSNP in order to achieve an average spacing of approximately 1 SNP every 5 kb across the IPO13 locus and its 20 kb flanking sequence (Figure 1a). Among non-Hispanic whites, all 10 SNPs had a minor allele frequency (MAF) of at least 0.05, and pair-wise LD high (median pair-wise D' 0.99, interquartile range of 0.98–1.0; see Figure 1b), suggesting very limited haplotype diversity. Indeed, the 10 SNP form only four common haplotypes (Figure 1c), which can be unambiguously classified by several possible combinations of three tagging-SNPs (one representative set denoted with arrowheads in Figure 1c). The genotyped SNP capture nearly all reported common variation at the IPO13 locus, in that they efficiently tag (r2 > 0.80) all but two of the 21 SNPs with available genotype information in the HapMap families of northern and western European ancestry. This high degree of LD implies substantial redundancy with regard to the number of independent observations made in the association studies to be described below. Using the spectral decomposition of matrices (see Methods and references [25] and [26]) we estimated that the 10 genotyped variants effectively represent only 6 independent markers for association testing.

Bottom Line:
In airway epithelial cells, inhibition of IPO13 expression prevents nuclear entry of GR and abrogates anti-inflammatory effects of glucocorticoids.This improvement was similar to that among children treated with long-term inhaled corticosteroids.IPO13 variation is associated with improved AHR in asthmatic children.

Background: Glucocorticoid function is dependent on efficient translocation of the glucocorticoid receptor (GR) from the cytoplasm to the nucleus of cells. Importin-13 (IPO13) is a nuclear transport receptor that mediates nuclear entry of GR. In airway epithelial cells, inhibition of IPO13 expression prevents nuclear entry of GR and abrogates anti-inflammatory effects of glucocorticoids. Impaired nuclear entry of GR has been documented in steroid-non-responsive asthmatics. We hypothesize that common IPO13 genetic variation influences the anti-inflammatory effects of inhaled corticosteroids for the treatment of asthma, as measured by change in methacholine airway hyperresponsiveness (AHR-PC20).

Methods: 10 polymorphisms were evaluated in 654 children with mild-to-moderate asthma participating in the Childhood Asthma Management Program (CAMP), a clinical trial of inhaled anti-inflammatory medications (budesonide and nedocromil). Population-based association tests with repeated measures of PC20 were performed using mixed models and confirmed using family-based tests of association.

Results: Among participants randomized to placebo or nedocromil, IPO13 polymorphisms were associated with improved PC20 (i.e. less AHR), with subjects harboring minor alleles demonstrating an average 1.51-2.17 fold increase in mean PC20 at 8-months post-randomization that persisted over four years of observation (p = 0.01-0.005). This improvement was similar to that among children treated with long-term inhaled corticosteroids. There was no additional improvement in PC20 by IPO13 variants among children treated with inhaled corticosteroids.

Conclusion: IPO13 variation is associated with improved AHR in asthmatic children. The degree of this improvement is similar to that observed with long-term inhaled corticosteroid treatment, suggesting that IPO13 variation may improve nuclear bioavailability of endogenous glucocorticoids.